ABSTRACT: Project 3-Mechanism-based Design of Combination Therapies for Pancreatic Cancer Project 3 develops mechanism and imaging-based combinations with photodynamic therapy (PDT) using novel nanoconstructs (NCs) in preclinical models of pancreatic cancer (PanCa), a disease with dismal statistics and tenacious resistance to current therapies. The promise of PDT in clinical and preclinical studies for PanCa in the previous cycle, our own findings in the current cycle, and collaborations within and outside the Program for efficient clinical translation, motivate the current investigations. The underlying hypothesis recognizes that the multiple growth/survival pathways of cancer development and progression demand an approach to combination treatments that exploits interactive mechanisms to achieve meaningful improvements in PanCa management. The strategy is to design combinations in which the first treatment primes/sensitizes the cancer cell for the second and can also be co-delivered, if warranted, for synergistic outcomes. The goals of the Project will be realized in 4 aims, interact heavily with the clinical projects, and build on our published and preliminary data showing superior control of local and metastatic PanCa with certain PDT-based combinations. Aim 1 will establish, in a genetically engineered mouse (GEM) model (Bardeesy Lab), the optimal schedule for a new combination treatment with (benzoporphyrin derivative, BPD)-PDT (FDA approved for AMD, in clinical studies for PanCa) and MM398, (liposomal irinotecan, Merrimack Pharma) a topisomerase I inhibitor that is FDA approved for colorectal cancer and is in phase III PanCa clinical trials. Assisted by a collaboration with Merrimack Pharma, the results of the PDT + MM-398 combination from Aim 1 will be rapidly translated within the funding cycle to clinical studies via Project 2, and could significantly impact the management of PanCa. Recognizing the need for appropriately timed and targeted combinations and based on preliminary data, Aim 2 takes a more forward-looking approach to synthesize EGFR-targeted multi-inhibitor containing liposomal NCs (TLNCs) for co-delivery of BPD and either a chemotherapeutic (SN-38) or a receptor tyrosine kinase inhibitor (XL184, a dirty inhibitor of VEGFR2, c-MET and EGFR pathways) to target key PanCa molecular pathways. To further enhance crosstalk within the Program, TLNCs containing Erlotinib will be developed for preclinical evaluation in non-melanoma skin cancers via Project 1 for eventual testing in humans. The optimal surface density of Erbitux will be established in vivo in collaboration with Project 4 and Core C. Aim 3 will test the optimized SN-38/XL184 TLNCs in sophisticated 3D heterocellular models that replicate stromal-cancer cell interactions, and will identify the most cytotoxic and selective constructs for testing in vivo. Aim 4 will evaluate the optimal cell line-specific TLNC from Aim 3 in orthotopic models of PanCa to assess acute tumor burden reduction (local and metastatic) with Core B and survival enhancement following combination treatment (PDT + SN-38/XL184). These novel targeted multi-agent constructs will form the basis of future clinical trials. Cores B and C provide imaging, pathology and statistical support.